Method for treating dyskinesia

ABSTRACT

The present invention is directed to the use of a class of peptide compounds for treating primary or/and secondary dyskinesias such as tardive dyskinesia.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional 60/571,932, filed May 18, 2004.

The present invention is directed to the use of a class of peptide compounds for treating primary or/and secondary dyskinesias such as tardive dyskinesia.

Certain peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS disorders. These peptides which are described in the U.S. Pat. No. 5,378,729 have the Formula (Ia):

wherein

-   -   R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,         aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower         alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower         alkyl, and R is unsubstituted or is substituted with at least         one electron withdrawing group or electron donating group;     -   R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl,         aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic,         lower cycloalkyl, lower cycloalkyl lower alkyl, each         unsubstituted or substituted with an electron donating group or         an electron withdrawing group; and     -   R₂ and R₃ are independeritly hydrogen, lower alkyl, lower         alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,         heterocyclic lower alkyl, lower alkyl heterocyclic, lower         cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and         R₃ may be unsubstituted or substituted with at least one         electron withdrawing group or electron donating group;     -   Z is O, S, S(O)_(a), NR₄, PR₄ or a chemical bond;     -   Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower         alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower         alkyl, and Y may be unsubstituted or substituted with an         electron donating group or an electron withdrawing group,         provided that when Y is halo, Z is a chemical bond, or     -   ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,         SNR₄R₇, NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

-   -   R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl,         aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R₄,         R₅ and R₆ may be unsubstituted or substituted with an electron         withdrawing group or an electron donating group; and     -   R₇ is R₆ or COOR₈ or COR₈;     -   R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl         or alkyl group may be unsubstituted or substituted with an         electron withdrawing group or an electron donating group; and     -   n is 1-4; and     -   a is 1-3.

U.S. Pat. No. 5,773,475 also discloses additional compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3-methoxy-propionamide having the Formula (IIa):

wherein

-   -   Ar is aryl which is unsubstituted or substituted with halo; R₃         is lower alkoxy; and R₁ is methyl.

The patents U.S. Pat. No. 5,378,729 and U.S. Pat. No. 5,773,475 are hereby incorporated by reference. However, neither of these patents describes the use of these compounds as specific antidyskinetic agents.

WO 02/074297 relates to the use of a compound according to Formula (IIa) wherein Ar is phenyl which may be substituted by at least one halo, R₃ is lower alkoxy containing 1-3 carbon atoms and R₁ is methyl for the preparation of pharmaceutical compositions useful for the treatment of allodynia related to peripheral neuropathic pain.

WO 02/074784 relates to the use of a compound having Formula (Ia) or/and Formula (IIa) showing antinociceptive properties for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain, e.g. rheumatoid arthritic pain or/and secondary inflammatory osteo-arthritic pain.

Dyskinesias are a group of disorders often involving the basal ganglia in which unwanted, superfluous movements occur. Defects in the basal ganglia may results in brisk, jerky, purposeless movements that resemble fragments of voluntary movements. Dyskinesias may include any combination of involuntary, rapid, randomly irregular jerky movements (chorea); relatively slow, writhing motions that appear to flow into one another (athetosis); increased muscle tone with repetitive, twisting, patterned movements and distorted posturing (dystonia); and uncontrollable flinging movements of an arm, a leg, or both (ballismus).

Primary dyskinesias occur in a number of different diseases. Sydenham's chorea is a disease usually associated with a toxic or infectious disorder that apparently causes temporary dysfunction of the corpus striatum and usually affects children. Huntington's chorea is a dominant hereditary disorder that begins in middle life and causes mental deterioration and progressive degeneration of the corpus striatum in affected individuals. Cerebral palsy is a general term referring to defects on motor functions or coordination resulting from several types of brain damage, which may be caused by abnormal brain development or birth-related injury. Some symptoms of cerebral palsy such as athetosis are related to basal ganglia dysfunction.

Secondary dyskinesias are observed in various diseases either as a secondary symptom (head injury, multiple sclerosis) or as a consequence of drug treatments. Parkinson's disease (PD), characterized by muscular rigidity, loss of facial expression, tremor, a slow, shuffling gait, and general lack of movement, is caused by a dysfunction in the substantia nigra. The increased muscular rigidity in Parkinson's disease results from defective inhibitions of some of the basal ganglia by the substantia nigra. In this disease, dopamine, an inhibitory neurotransmitter substance, is deficient. Parkinson's disease can be treated with levodopa (L-dopa), a precursor to dopamine. L-DOPA induces unwanted, excessive and abnormal dyskinesias. Eventually, more than 50% of PD patients on long-term L-DOPA treatment will be affected with excessive, uncontrolled movement. The most common types of dyskinesias are chorea and dystonia, and these are often mixed.

Tardive dyskinesia is a neurological syndrome caused by the long-term use of neuroleptic drugs. Neuroleptic drugs are generally prescribed for psychiatric disorders, a well as for some gastrointestinal and neurological disorders. Tardive. dyskinesia is characterized by repetitive, involuntary, purposeless movements. Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk may also occur. Impaired movements of the fingers may appear as though the patient is playing an invisible guitar or piano.

The mechanisms of dyskinesias are poorly understood. Current treatments use a variety of pharmacological, surgical, physical and psychological approaches. However, the evidence for many of the treatments is still limited.

The use of compounds of Formula (Ib) or/and Formula (IIb) for treatment of dyskinesias has not been reported. Thus, the present invention concerns the use of said compounds of Formulae (Ib) or/and (IIb) for the preparation of a pharmaceutical composition for the prevention, alleviation or/and treatment of primary dyskinesias such as Huntington's chorea or cerebral palsy or/and secondary dyskinesias such as tardive or L-DOPA-induced dyskinesias. The dyskinesia forms to be treated with the compounds of the invention include chorea, athetosis, dystonia, ballismus or combinations thereof.

Surprisingly, application of compounds (Ib) or/and (IIb), particularly (R)-2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927) exhibited a significant efficacy in reducing tardive dyskinesia in mice. Thus, the compounds are useful as medicament for treating dyskinesias.

A compound according to the invention has the general Formula (Ib)

wherein

-   -   R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,         aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower         alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower         alkyl, and R is unsubstituted or is substituted with at least         one electron withdrawing group, and/or at least one electron         donating group;     -   R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl,         aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl         heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl         lower alkyl, each unsubstituted or substituted with at least one         electron donating group and/or at least one electron withdrawing         group;     -   and     -   R₂ and R₃ are independently hydrogen, lower alkyl, lower         alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo,         heterocyclic, heterocyclic lower alkyl, lower alkyl         heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or         Z-Y wherein R₂ and R₃ may be unsubstituted or substituted with         at least one electron withdrawing group and/or at least one         electron donating group;     -   Z is O, S, S(O)_(a), NR₄, NR′₆, PR₄ or a chemical bond;     -   Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower         alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower         alkyl, lower alkyl heterocyclic and Y may be unsubstituted or         substituted with at least one electron donating group and/or at         least one electron withdrawing group, provided that when Y is         halo, Z is a chemical bond, or     -   ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,         SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇ or N⁺R₅R₆R₇,

-   -   R′₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl         which may be unsubstituted or substituted with at least one         electron withdrawing group or/and at least one electron donating         group;     -   R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl,         aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R₄,         R₅ and R₆ may independently be unsubstituted or substituted with         at least one electron withdrawing group or/and at least one         electron donating group;     -   R₇ is R₆ or COOR₈ or COR₈, which R₇ may be unsubstituted or         substituted with at least one electron withdrawing group or/and         at least one electron donating group;     -   R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl         or alkyl group may be unsubstituted or substituted with at least         one electron withdrawing group or/and at least one electron         donating group; and     -   n is 1-4; and     -   a is 1-3.

Preferably the compound according to the present invention has the general Formula (IIb)

wherein

-   -   Ar is aryl, especially phenyl, which is unsubstituted or         substituted with at least one halo; R₃ is —CH₂-Q, wherein Q is         lower alkoxy; and R₁ is lower alkyl, especially methyl.

The present invention is also directed to a pharmaceutical composition comprising a compound according to Formula (Ib) or/and Formula (IIb) useful for the prevention, alleviation or/and treatment of dyskinesias, e.g. primary dyskinesias or dyskinesias associated with different types of disorders, e.g. toxic, infectious, hereditary, and/or neurological disorders and/or with drug treatment. More particularly, the compounds are useful for the prevention, alleviation or/and treatment of Sydenham's chorea, Huntington's chorea, cerebral palsy, secondary symptoms of head injury or multiple sclerosis, or dyskinesias associated with the treatment of Parkinson's disease, e.g. with L-DOPA, or with the treatment of psychiatric disorders with neuroleptic drugs.

The “lower alkyl” groups when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, and may be straight chain or branched. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl, and the like.

The “lower alkoxy” groups are lower alkoxy containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, and may be straight chain or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

The “aryl lower alkyl” groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

The term “aryl”, when used alone or in combination, refers to an aromatic group which contains from 6 up to 18 ring carbon atoms and up to a total of 25 carbon atoms and includes the polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. A polynuclear aromatic compound as used herein, is meant to encompass bicyclic and tricyclic fused aromatic ring systems containing from 10-18 ring carbon atoms and up to a total of 25 carbon atoms. The aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. The aryl group also includes groups like ferrocenyl. Aryl groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups as described below.

“Lower alkenyl” is an alkenyl group containing from 2 to 6 carbon atoms and at least one double bond. These groups may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1,3 or 2,4-pentadienyl, and the like.

The term “lower alkynyl” is an alkynyl group containing 2 to 6 carbon atoms and may be straight chained as well as branched. It includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.

The term “lower cycloalkyl” when used alone or in combination is a cycloalkyl group containing from 3 to 18 ring carbon atoms and up to a total of 25 carbon atoms. The cycloalkyl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. The cycloalkyl may be completely saturated or partially saturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl, and the like. Cycloalkyl includes the cis or trans forms. Cycloalkyl groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups as described below. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.

The term “electron-withdrawing and electron donating” refer to the ability of a substituent to withdraw or donate electrons, respectively, relative to that of hydrogen if the hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, N.Y., pp. 16-18 (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include halo, including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl such as trifluoromethyl, aryl lower alkanoyl, carbalkoxy and the like. Electron donating groups include such groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the like; amino, lower alkylamino, di(loweralkyl)amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide(lower alkyldithio) and the like. One of ordinary skill in the art will appreciate that some of the aforesaid substituents may be considered to be electron donating or electron withdrawing under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.

The term “halo” includes fluoro, chloro, bromo, iodo and the like.

The term “acyl” includes lower alkanoyl containing from 1 to 6 carbon atoms and may be straight chains or branched. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.

As employed herein, a heterocyclic group contains at least one sulfur, nitrogen or oxygen ring atom, but also may include several of said atoms in the ring. The heterocyclic groups contemplated by the present invention include heteroaromatics and saturated and partially saturated heterocyclic compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. They may preferably contain up to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms. The heterocyclics are also intended to include the so-called benzoheterocyclics. Representative heterocyclics include furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles, such as the N-oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like. Heterocyclic groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups.

The preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a 5 or 6-membered heterocyclic compound. The especially preferred heterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The most preferred heterocyclics are furyl and pyridyl.

The preferred compounds are those wherein n is 1, but di (n=2), tri (n=3) and tetrapeptides (n=4) are also contemplated to be within the scope of the invention.

The preferred values of R is aryl lower alkyl, especially benzyl especially those wherein the phenyl ring thereof is unsubstituted or substituted with electron donating groups or/and electron withdrawing groups, such as halo (e.g., F).

The preferred R₁ is H or lower alkyl. The most preferred R₁ group is methyl.

The preferred electron donating substituents or/and electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl) amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide” encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio. Especially preferred electron donating or/and electron withdrawing groups are halo or lower alkoxy, most preferred are fluoro or methoxy. These preferred substituents may be present on any one of the groups in Formula (Ib) or/and (IIb), e.g. R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₅₀and/or R₈ as defined herein.

The ZY groups representative of R₂ and R₃ include hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt, hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino (—NH—OH), lower alkoxy amino [(NHOR,₁₈) wherein R₁₈ is lower alkyl], N-lower alkylhydroxyl amino [(NR₁₈)OH wherein R₁₈ is lower alkyl], N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈ and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂); alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino, (e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamino.

The preferred heterocyclic groups representative of R₂ and R₃ are monocyclic 5- or 6-membered heterocyclic moieties of the formula:

or those corresponding partially or fully saturated form thereof wherein n is 0 or 1; and

-   -   R₅₀ is H or an electron withdrawing group or electron donating         group;     -   A, E, L, J and G are independently CH, or a heteroatom selected         from the group consisting of N, O, S;     -   but when n is 0, G is CH, or a heteroatom selected from the         group consisting of NH, O and S with the proviso that at most         two of A, E, L, J and G are heteroatoms.

When n is 0, the above heteroaromatic moiety is a five membered ring, while if n is 1, the heterocyclic moiety is a six membered monocyclic heterocyclic moiety. The preferred heterocyclic moieties are those aforementioned heterocyclics which are monocyclic.

If the ring depicted hereinabove contains a nitrogen ring atom, then the N-oxide forms are also contemplated to be within the scope of the invention.

When R₂ or R₃ is a heterocyclic of the above formula, it may be bonded to the main chain by a ring carbon atom. When n is 0, R₂ or R₃ may additionally be bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g., phenyl, aryl alkyl, e.g., benzyl and alkyl.

It is to be understood that the preferred groups of R₂ and R₃ may be unsubstituted or mono or poly substituted with electron donating or/and electron withdrawing groups. It is preferred that R₂ and R₃ are independently hydrogen, lower alkyl, which is either unsubstituted or substituted with electron withdrawing groups or/and electron donating groups, such as lower alkoxy (e.g., methoxy, ethoxy, and the like), N-hydroxylamino, N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyl and alkylhydroxyamino.

It is preferred that one of R₂ and R₃ is hydrogen.

It is preferred that n is one.

It is more prefered that n=1 and one of R₂ and R₃ is hydrogen. It is especially preferred that in this embodiment, R₂ is hydrogen and R₃ is lower alkyl or ZY;

-   -   Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZY is         NR₄NR₅R₇, NR₄OR₅,

In another especially preferred embodiment, n=1, R₂ is hydrogen and R₃ is lower alkyl which may be substituted or unsubstituted with an electron donating or electron withdrawing group, NR₄OR₅, or ONR₄R₇,

In yet another especially preferred embodiment, n=1, R₂ is hydrogen and R₃ is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR₄R₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R₁ is lower alkyl. In this embodiment it is most preferred that aryl is phenyl, which is unsubstituted or substituted with halo.

It is preferred that R₂ is hydrogen and R₃ is hydrogen, an alkyl group which is unsubstituted or substituted by at least an electron donating or electron withdrawing group or ZY. In this preferred embodiment, it is more preferred that R₃ is hydrogen, an alkyl group such as methyl, which is unsubstituted or substituted by an electron donating group, or NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or lower alkyl. It is preferred that the electron donating group is lower alkoxy, and especially methoxy or ethoxy.

It is preferred that R₂ and R₃ are independently hydrogen, lower alkyl, or ZY;

-   -   Z is O, NR₄ or PR₄;     -   Y is hydrogen or lower alkyl or     -   ZY is NR₄R₅R₇, NR₄OR₅, ONR₄R₇,

It is also preferred that R is aryl lower alkyl. The most preferred aryl for R is phenyl. The most preferred R group is benzyl. In a preferred embodiment, the aryl group may be unsubstituted or substituted with an electron donating or electron withdrawing group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halo, especially fluoro.

The preferred R₁ is lower alkyl, especially methyl.

It is more preferred that R is aryl lower alkyl and R₁ is lower alkyl.

Further preferred compounds are compounds of Formula (Ib) wherein n is 1; R₂ is hydrogen; R₃ is hydrogen, a lower alkyl group, especially methyl which is substituted by an electron donating or electron withdrawing group or ZY; R is aryl, aryl lower alkyl, such as benzyl, wherein the aryl group is unsubstituted or substituted with an electron donating or electron withdrawing group and R₁ is lower alkyl. In this embodiment, it is more preferred that R₃ is hydrogen, a lower alkyl group, especially methyl, which may be substituted by electron donating group, such as lower alkoxy, (e.g., methoxy, ethoxy and the like), NR₄OR₅ or ONR₄R₇ wherein these groups are defined hereinabove.

The most preferred compounds utilized are those of the Formula (IIb):

wherein

-   -   Ar is aryl, especially phenyl, which is unsubstituted or         substituted with at least one electron donating group or         electron withdrawing group, especially halo,     -   R₁ is lower alkyl, especially containing 1-3 carbon atoms; and     -   R₃ is as defined herein, but especially hydrogen, loweralkyl,         which is unsubstituted or substituted by at least an electron         donating group or electron withdrawing group or ZY. It is even         more preferred that R₃ is, in this embodiment, hydrogen, an         alkyl group which is unsubstituted or substituted by an electron         donating group, NR₄OR₅ or ONR₄R₇. It is most preferred that     -   R₃ is CH₂-Q, wherein Q is lower alkoxy, especially containing         1-3 carbon atoms; NR₄OR₅ or ONR₄R₇ wherein R₄ is hydrogen or         alkyl containing 1-3 carbon atoms, R₅ is hydrogen or alkyl         containing 1-3 carbon atoms, and R₇ is hydrogen or alkyl         containing 1-3 carbon atoms.

The most preferred R₁ is CH₃. The most preferred R₃ is CH₂-Q, wherein Q is methoxy.

The most preferred aryl is phenyl. The most preferred halo is fluoro.

The most preferred compounds include:

-   -   (R)-2-acetamido-N-benzyl-3-methoxy-propionamide;     -   O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;     -   O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;     -   N-acetyl-D-phenylglycine benzylamide;     -   D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid         benzylamide;     -   D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid         benzylamide.

It is to be understood that the various combinations and permutations of the Markush groups of R₁, R₂, R₃, R and n described herein are contemplated to be within the scope of the present invention. Moreover, the present invention also encompasses compounds and compositions which contain one or more elements of each of the Markush groupings in R₁, R₂, R₃, n and R and the various combinations thereof. Thus, for example, the present invention contemplates that R₁ may be one or more of the substituents listed hereinabove in combination with any and all of the substituents of R₂, R₃, and R with respect to each value of n.

The compounds utilized in the present invention may contain one or more asymmetric carbons and may exist in racemic and optically active forms. The configuration around each asymmetric carbon can be either the D or L form. It is well known in the art that the configuration around a chiral carbon atoms can also be described as R or S in the Cahn-Prelog-lngold nomenclature system. All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the present invention.

In the principal chain, there exists asymmetry at the carbon atom to which the groups R₂ and R₃ are attached. When n is 1, the compounds of the present invention is of the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈, R₅₀, Z and Y are as defined previously.

As used herein, the term configuration shall refer to the configuration around the carbon atom to which R₂ and R₃ are attached, even though other chiral centers may be present in the molecule. Therefore, when referring to a particular configuration, such as D or L, it is to be understood to mean the D or L stereoisomer at the carbon atom to which R₂ and R₃ are attached. However, it also includes all possible enantiomers and diastereomers at other chiral centers, if any, present in the compound.

The compounds of the present invention are directed to all the optical isomers, i.e., the compounds of the present invention are either the L-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂ and R₃ are attached). These stereoisomers may be found in mixtures of the L and D stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred.

More preferred is a compound of Formula (III) in the R configuration, preferably substantially enantiopure, wherein the substituent R is benzyl which is unsubstituted or substituted with at least one halo group, wherein

R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3 carbon atoms and wherein R₁ is methyl. Preferably R is unsubstituted benzyl or benzyl substituted with at least one halo group which is a fluoro group.

Depending upon the substituents, the present compounds may form addition salts as well. All of these forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric forms.

The manufacture of the utilized compounds is described in U.S. Pat. Nos. 5,378,729 and 5,773.475, the contents of both of which are incorporated by reference.

The compounds utilized in the present invention are useful as such as depicted in the Formulae (Ib) or/and (IIb) or can be employed in the form of salts in view of its basic nature by the presence of the free amino group. Thus, the compounds of Formulae (Ib) or/and (IIb) form salts with a wide variety of acids, inorganic and organic, including pharmaceutically acceptable acids. The salts with therapeutically acceptable acids are of course useful in the preparation of formulation where enhanced water solubility is most advantageous.

These pharmaceutically acceptable salts have also therapeutic efficacy. These salts include salts of inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids as well as salts of organic acids, such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids, benzenesulfonic), phosphoric, malonic, and the like.

The present invention is further directed to a method for the prevention, alleviation or/and treatment of a disease or condition as described above in a mammal, including a human being, comprising administering at least one compound of Formulae (Ib) or/and (IIb).

It is preferred that the compound utilized in the present invention is used in therapeutically effective amounts.

The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the patient under treatment, the age of the patient, the type of malady being treated. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. When the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. The compounds are useful in the same manner as comparable therapeutic agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents.

In a preferred embodiment, the compounds of the present invention are administered in amounts ranging from about 1 mg to about 100 mg per kilogram of body weight per day, more preferred in amounts ranging from about 1 mg to about 10 mg per kilogram of body weight per day. This dosage regimen may be adjusted by the physician to provide the optimum therapeutic response. Patients in need thereof may be treated with doses of the compound of the present invention of at least 50 mg/day, preferably of at least 200 mg/day, more preferably of at least 300 mg/day and most preferably of at least 400 mg/day. For example, a patient in need thereof may be treated with doses at a maximum of 6 g/day, more preferably a maximum of 1 g/day and most preferably a maximum of 600 mg/day. In some cases, however, lower or higher doses may be needed.

In another preferred embodiment, the daily doses are increased until a predetermined daily dose is reached which is maintained during the further treatment.

In yet another preferred embodiment, several divided doses may be administered daily or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation. For example, three doses per day may be administered, preferably two doses per day. It is more preferred to administer a single dose per day.

In yet another preferred embodiment, an amount of the compounds of the present invention may be administered which results in a plasma concentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak), calculated as an average over a plurality of treated subjects.

The compounds of Formulae (Ib) or/and (IIb) may be administered in a convenient manner, such as by oral, intravenous (where water soluble), intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v. administration is preferred.

The pharmaceutical composition of the present invention may be prepared for the treatment regimen as described above, in particular for the treatment with doses as described above, to effect plasma concentrations as described above, for administration periods or/and administration routes as specified in the embodiments of the present invention as described above.

In another preferred embodiment, the method of the present invention as described above for the treatment of a mammal including a human being in need thereof comprises administering a compound of the present invention in combination with administering a further active agent for the prevention, alleviation or/and treatment of dyskinesias or with an active agent for the prevention, alleviation and/or treatment of a disorder with which the occurence of dyskinesias is associated, e.g. L-dopa or a neuroleptic drug. The compound of the present invention and the further active agent(s) may be administered together, i.e. in a single dose form, or may be administered separately, i.e. in a separate dose form. Thus, the pharmaceutical composition of the present invention may comprise a compound of the present invention as defined above and may further comprise one or several active agents as indicated above. The pharmaceutical composition may comprise a single dose form or may comprise a separate dose form comprising a first composition comprising a compound of the present invention as defined above and a second and optionally a further composition comprising the further active agent.

The compounds of the present invention may be used for the preparation of a pharmaceutical composition as described above.

The compounds of Formulae (Ib) or/and (IIb) may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly into the fool of the diet. For oral therapeutic administration, the active compound of Formulae (Ib) or/and (IIb) may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% of active compound of Formulae (Ib) or/and (IIb). The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound of Formulae (Ib) or/and (IIb) in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention contains between about 10 mg and 6 g active compound of Formulae (Ib) or/and (IIb).

The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. For example, sustained release dosage forms are contemplated wherein the active ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.

The active compound may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying the freeze-drying technique plus any additional desired ingredient from previously sterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agent, isotonic and absorption delaying agents for pharmaceutical active substances as well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form or ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifics for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material an the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such as active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore described. A unit dosage form can, for example, contain the principal active compound in amounts ranging from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in from about 1 to about 750 mg/ml of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

As used herein the term “patient” or “subject” refers to a warm blooded animal, and preferably mammals, such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans. The preferred patient is a human.

The term “treat” refers to either relieving the pain associated with a disease or condition or alleviating the patient's disease or condition.

The compounds of the present invention are administered to a patient suffering from the aforementioned type of dyskinesia in an anti-dyskinetic effective amount. These amounts are equivalent to the therapeutically effective amounts described hereinabove.

The following example shows the properties of SPM 927 in reducing unwanted chewing movements in reserpine-induced tardive dyskinesia.

The used substance was SPM 927 which is the synonym for Harkoseride. The standard chemical nomenclature is (R)-2-acetamide-N-benzyl-3-methoxypropionamide. The international non-proprietory name of SPM 927 is lacosamide.

EXAMPLE

The Effects of SPM 927 on Reserpine-Induced Tardive Dyskinesia in Mice

OBJECTIVES

The objective of the present study is to demonstrate that SPM 927 reduces dyskinesias as determined in an animal model for tardive dyskinesia induced by repeated administration of reserpine (1) in mice.

MATERIALS AND METHODS

Male CD1 mice (Charles River Laboratories, France), about 3 month-old were used. During the acclimatization period, animals were housed 5 per cage, in Makrolon type IlIl cages, in the animal room (temperature: 20±2° C., humidity: minimum 45%, air changes: >12 per hour, light/dark cycle of 12 h/12 h [on at 7:00 A.M:]. Animals were allowed a minimum of 5 days period before experiment for acclimatization.

Animals received certified food (RM1 [E] SQC, Trouw Nutrition France, Vigny, France, ref. 811002) and water (tap water in water bottle) ad libitum. Water was analysed once a month for chemical contaminants and at least every three months for bacterial contaminants. Mice were placed on certified sawdust bedding in their cages (Goldchips Litalabo, ref. 891021, Trouw Nutrition France, Vigny, France).

Reserpine (Sigma) was dissolved in glacial acetic acid, diluted in water and administered s.c. at 1 mg/kg. 2 injections were given separated by 48 h. SPM 927 was studied at 3 doses (3, 10 and 30 mg/kg; i.p.) given as a single injection. Clonazepam was administered at 1 mg/kg, i.p. (3).

Reserpine was given twice (Day 1 and Day 3) and SPM 927 was administered 24 h after the last injection of reserpine (Day 4). Behavioral assessment was carried out 1 hour after drug injection (for 10 min). For the behavioral assessment, animals were placed in a plexiglass cage and after 5 min period of habituation, vacuous chewing movements (VCM) were counted for 10 min. VCM occurring during a grooming period were not taken into account.

Results are expressed as means±S.E.M.s of ten individual values. Statistical analyses was done with ANOVA (one way) and Dunnett's t-test. Significance was considered as p<0.05.

The experiment includes the following treatment groups:

Group 1: Control (n = 10) Group 2: Vehicle (n = 10) Group 3: Reference compound (Clonazepam) (n = 10) Group 4: SPM 927 (3 mg/kg) (n = 10) Group 5: SPM 927 (10 mg/kg) (n = 10) Group 6: SPM 927 (30 mg/kg) (n = 10)

RESULTS

It was found that SPM 927 attenuates reserpine induced vacuous chewing movements.

The results are summarized in Table 1.

The results show that repeated reserpine treatments induced an increase in the number of vacuous chewing movements in the vehicle-treated group when compared to the control-treated group (p<0.001 versus control animals).

SPM 927, given at 10 and 30 mg/kg, reduced the number of vacuous chewing movements. This effect was statistically significant at the highest dose tested (p<0.05 versus vehicle group). At the lowest dose of 3 mg/kg, SPM 927 had little or no effect on reserpine-induced dyskinesia.

TABLE 1 Effects of SPM 927 on the number of vacuous chewing movements 1 hour post-administration. VCM frequency per 10 min. Treatment Mean ± S.E.M. Control (Vehicle for reserpine + vehicle)  1.4 ± 0.8*** Reserpine, 1 mg/kg + vehicle, 10 mL/kg 41.4 ± 6.4 Reserpine, 1 mg/kg + SPM 927, 3 mg/kg 48.6 ± 10.6 Reserpine, 1 mg/kg + SPM 927, 10 mg/kg 26.6 ± 5.7 Reserpine, 1 mg/kg + SPM 927, 30 mg/kg 23.9 ± 7.9* Values are Means ± S.E.M.s of 10 values. Data were analyzed for statistical significance by Kruskal-Wallis test followed by Mann-Whitney U-test. *p < 0.05, ***p < 0.001 versus vehicle group (reserpine + vehicle)

CONCLUSION

These results demonstrate that SPM 927 and related compounds are useful for the treatment of dyskinesias including primary dyskinesias (Huntington or Sydenham's chorea), secondary dyskinesias as observed in patients with head injury or multiple sclerosis and drug treatment induced dyskinesias e.g. L-DOPA- or neuroleptic-induced dyskinesia. 

1. A method for alleviating and/or treating tardive dyskinesia in a subject, the method comprising administering to the subject the compound (R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the compound is administered in a dose of at least 50 mg/day.
 3. The method of claim 1, wherein the compound is administered in a dose not greater than 6 g/day.
 4. The method of claim 1, wherein the compound is administered in increasing daily doses until a predetermined daily dose is reached which is maintained during further treatment.
 5. The method of claim 1, wherein the compound is administered in not more than three doses per day.
 6. The method of claim 1, wherein the compound is administered in a pharmaceutical composition resulting in a plasma concentration of the compound of 0.1 to 15 μg/ml trough and 5 to 18.5 μg/ml (peak), calculated as an average over a plurality of treated subjects.
 7. The method of claim 1, wherein the compound is administered orally.
 8. The method of claim 1, wherein the tardive dyskinesia is associated with a toxic, infectious, hereditary and/or psychiatric disorder and/or with drug treatment.
 9. The method of claim 1, further comprising administering to the subject a further active agent for alleviation and/or treatment of dyskinesia and/or a further active agent for alleviation and/or treatment of a disorder with which the tardive dyskinesia is associated.
 10. The method of claim 9, wherein the compound and said further active agent(s) are administered in a single pharmaceutical composition.
 11. The method of claim 1, wherein the subject is a mammal.
 12. The method of claim 11, wherein the subject is human.
 13. A pharmaceutical composition comprising (a) the compound (R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof in an amount effective to alleviate and/or treat tardive dyskinesia, and (b) at least one of a further active agent for alleviation and/or treatment of dyskinesia and/or a further active agent for alleviation and/or treatment of a disorder with which the tardive dyskinesia is associated.
 14. A therapeutic combination comprising (a) the compound (R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof in an amount effective to alleviate and/or treat tardive dyskinesia, and (b) at least one of a further active agent for alleviation and/or treatment of dyskinesia and/or a further active agent for alleviation and/or treatment of a disorder with which the tardive dyskinesia is associated; the combination being contained in a single pharmaceutical composition or in separate pharmaceutical compositions respectively comprising said compound or salt thereof (a) and said further active agent(s)(b). 